| The molecular clock maintains energy stability by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and while rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes, it is not known how the circadian clock may affect metabolism at the level of the pancreatic islet. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of main components of the circadian transcription network, such as Per2, Bmal1, Dbp and RevErbalpha. The phase of oscillation of islet genes involved in growth, glucose metabolism, and insulin signaling is delayed in circadian mutant mice, revealing a role of the clock in synchronizing pancreatic rhythms. Genetic models of global circadian disruption in both Clock and Bmal1 mutant mice reveal impaired glucose tolerance, reduced insulin secretion, and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide defects in the expression of genes involved in islet growth, survival, and vesicle assembly. Remarkably, conditional ablation of the pancreatic clock causes diabetes mellitus due to disruption of glucose-stimulated insulin secretion from islets of circadian mutant mice. Cellular analyses showed normal levels of calcium influx and a refractory response to both cyclase activators and potassium channel agonists, indicating defective beta-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a primary role for the islet clock in mammalian glucose homeostasis, priming the beta-cell to optimize insulin secretion in anticipation of the sleep-wake/feeding-fasting cycle, and demonstrate how elimination of the clock in pancreatic islets initiates a cascade of cellular failure and organismal pathology, triggering the onset of diabetes mellitus. |
